Interleukin-5 production in vivo appears to have a unique role in the production, activation, and localization of eosinophils in a variety of allergic conditions. The current paradigm suggests that allergen-specific Th2 cells are the key source for the IL-5 production. However, multiple allergic disorders have been associated with elevated IL-5 without an increase in the other Th2-derived cytokines. This application provides preliminary data indicating that distinct subpopulations of NK cells are a separate potent source of IL-5 and that their depletion in vivo attenuates certain forms of eosinophil-associated inflammation. Several hypotheses have been formulated from these preliminary observations: (1) early cytokine exposure influences the differentiation of progenitor NK cells into distinct and committed IL-5 high or low producing subsets; (2) the signaling requirements eliciting IL-5 production from NK cells is fundamentally different from that required for Th2 cells; and (3) NK cell-derived IL-5 significantly influences the development of eosinophil-associated inflammation. These hypotheses are going to be tested in the following aims: (1) characterize the regulation of distinct IL-5 high and low producing NK cell subpopulations; (2) evaluate the role of IL-5 producing NK cell subpopulations in murine models of allergic inflammation; and (3) analyze whether clinical pulmonary diseases characterized by eosinophilia are associated with activated, IL-5 producing NK cells. Taken together, these studies will provide new insights on the regulation of this novel cytokine-producing subpopulation, their role in the pathogenesis of eosinophil-associated inflammation, and their clinical relevance to allergic disorders.